Cancer is a disease that arises from a prolonged period of genetic instability that extends the lifespan of a normal cell. The triggering event that marks the beginning of this period is variable between cell types, but commonly is the acquisition of a mutation in a tumor suppressor gene such as p53 or Rb, a mutation in a proto-oncogene such as KRAS or myc, or infection of a cell with an oncogenic virus such as HPV16 or EBV. Whatever the origin, cells that acquire mutations in genes that enable them to escape normal growth controls or cell death pathways become more likely to acquire additional mutations. Once a cell has acquired “enough” mutations, typically thought to be at least six, it no longer is responsive to intrinsic or extrinsic signals that would restrain its growth or trigger apoptosis.
Because tumors arise from host cells, the body's immune system is initially tolerant to those cells. The acquisition of tumorigenic mutations may or may not lead to production of a mutated protein containing an epitope that is sufficiently non-self to become immunogenic. If a cell acquires an immunogenic mutation, it can be sought out and destroyed by the host immune system, a process known as immunosurveillance (Smyth et al., Adv Immunol 2006, 90:1-50). Murine studies have provided support for the immune surveillance hypothesis (Dunn et al., Nat Immunol 2002, 3:991-998; Shankaran et al., Nature 2001, 410:1107-1111; and Dunn et al., Annu Rev Immunol 2004, 22:329-360), and also suggested that innate in addition to so-called adaptive immune responses may facilitate rejection of immunogenic tumors (Unni et al., Proc Natl Acad Sci USA 2008, 105:1686-1691; Taieb et al., Nat Med 2006, 12:214-219; and Raulet and Guerra, Nat Rev Immunol 2009, 9:568-580). Innate responses can be evoked through induced expression of NK activating signals such as NKG2D ligand expression or following DNA damage incurred as a result of mutagenic or viral processes. Some cells that acquire immunogenic mutations also gain the capacity to engage normal immune regulatory systems that dampen anti-self immune responses (Rabinovich et al., Annu Rev Immunol 2007, 25:267-296). The pathways driving the activation of host regulatory mechanisms are poorly understood. Still other cells may gain a number of oncogenic mutations without ever producing an immunogenic peptide that leads to activation of the host immune system. Therefore, tumor cells that produce an immunogenic peptide during their transformation must continuously evade anti-tumor immune responses in order to survive, whereas tumors that become transformed without activating the immune system may not rely on such immune regulatory mechanisms for survival.